AIDS INFORMATION NEWSLETTER
AIDS Information Center
VA Medical Center, San Francisco
The dynamics of HIV-1 replication in vivo strongly suggest
that early, aggressive antiretroviral therapy is needed to minimize
the negative consequences of HIV replication. Recent findings have
shown that combinations of potent agents can reduce circulating
free virus to undetectable levels in many individuals for prolonged
periods of time. A theoretical possibility has also been raised
that, in individuals treated at very early stages (i.e., before
seroconversion), HIV infection might even be eradicated, because,
after some years of theoretical "zero-replication," HIV infection
might "burn itself out," as chronically infected cells die off.
Long-term data are yet to come, however, and we know that HIV might
survive, even in the presence of powerful treatment, within
latently infected cells in tissue, bone marrow, and other
macrophage-rich tissues and organs, or in "sanctuary sites"
inaccessible to treatment.
Indeed, the best opportunity to accomplish maximal suppression
of virus replication and to minimize the risk of drug resistance
is to use potent combinations in individuals with no prior history
of antiretroviral use. However, very early intervention is,
unfortunately, not possible for the majority of our patients.
Careful therapeutic intervention should therefore be designed with
the aim of keeping HIV viral load at undetectable or minimal levels
indefinitely to prevent disease progression and transform HIV
disease into a chronic disease with minimal levels indefinitely,
to prevent disease progression and transform HIV disease into a
chronic disease with minimal negative impact on the duration and
quality of life of the infected persons.
With that as an aim, then, rational criteria must be adopted
for 1) selecting drug combinations with the best chance of long-
term efficacy, but also 2) preserving subsequent therapeutic
options if the initial choice fails to achieve the desired results.
Because any choice has an impact on later options, therapeutic
plan design should include, whenever possible, both initial therapy
and predefined alternative antiretroviral regimens. Unfortunately,
new resistance mutations continue to be discovered and many of the
promising new drugs seem to be better for first-line use.
Therefore, the issue of the many patients who are failing agressive
antiretroviral regimens remains unsolved.
As far as resistance is concerned, a number of rules should
be followed in planning therapeutic strategies:
1) Sequential use of combination drugs that share clear
cross-resistance phenomena should be avoided.
2) Potent antiretroviral drugs to which HIV readily develops
high-level resistance should not be used in regimens that are expected to
yield incomplete suppression of viral replication.
3) Decisions to alter antiretroviral therapy need to be made
carefully, because the number of effective drugs available is still very
limited. In fact, an increase in HIV RNA levels in persons receiving fully
suppressive antiretroviral therapy can be due to a number of factors, one
of which is lack of full adherence to a particular drug combination. In
fact, the complexity of the regimens may jeopardize the expected benefits
of potent combinations started early. The problem of drug resistance, far
from being overcome, might dramatically strike back.
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